Substituted phenylsulfamyl salicyclic acids and derivatives thereof in the treatment of inflammation

ABSTRACT

Substituted phenyl sulfamyl or sulfonamido salicylic acids and non-toxic pharmaceutical accepted salts, esters, amides and various derivatives thereof are claimed. Also a method of treating inflammation which comprises administering various substituted phenyl sulfamyl or sulfonamido salicylic acids and the various derivatives are also claimed. The substituted phenyl sulfamyl or sulfonamido salicylic acids described herein have anti-inflammatory, anti-pyretic and analgesic activity.

United States Patent Shen et al.

[151 3,700,773 [451 Oct. 24, 1972 [54] SUBSTITUTED PI-IENYLSULFAMY L SALICYCLIC ACIDS AND DERIVATIVES THEREOF IN THE TREATIVIENT OF INFLAMMATION [72] Inventors: Tsung-Ying Shen; Bruce E. Witzel; Gordon L. Walford, all of Westfield,

[73] Assignee: Merck & Co., Inc., Rahway, NJ.

[22] Filed: June 25, 1969 211 Appl. No.: 836,605

[52] US. Cl. ..424/230, 424/248, 260/519 [51] Int. Cl. ..A6lk 27/00 [58] Field of Search ..424/230 [56] References Cited UNITED STATES PATENTS 3,657,430 4/ 1972 Shen et al. ..424/267 Primary Exairiiner stanley J. Friedman Attorney-Michael C. Sudol, Jr., Harry E. Westlake, Jr. and 1. Louis Wolk [57] ABSTRACT Substituted phenyl sulfamyl or sulfonamido salicylic acids and non-toxic pharmaceutical accepted salts, esters, amides and various derivatives thereof are claimed. Also a method of treating inflammation which comprises administering various substituted phenyl sulfamyl or sulfonamido salicylic acids and the various derivatives are also claimed. The substituted phenyl sulfamyl or sulfonamido salicylic acids described herein have anti-inflammatory, anti-pyretic and analgesic activity.

4 Claims, N0 Drawings SUBSTITUTED PHENYLSULFAMYL SALICYCLIC ACIDS AND DERIVATIVES THEREOF IN THE TREATMENT OF INFLAMMATION BACKGROUND OF THE INVENTION The development of anti-inflammatory compounds in the past two decades has seen the growth of a great many new drugs. Most of these have been steroids of the l l-oxygenated pregnane series. These, while highly effective, have the drawback of causing many side effects. There is a need in the market for equally effective compounds of much simpler structure and having less side effects.

SUMMARY OF THE INVENTION Generally this invention relates to new substitutedphenylsulfamyl or sulfonamido salicylic acids and a derivative thereof and the use of these acids and derivatives as a method of treating inflammation. Compounds covered by this invention are useful in that they have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation. in addition, some of them have a useful degree of anti-pyretic and analgesic activity.

DESCRIPTION AND PREFERRED EMBODIMENTS The invention relates to the use of new substitutedphenylsulfamyl or sulfonamido salicylic acids and derivatives thereof in treating inflammation. More specifically, the invention relates to the use of the following compounds (Formula I) as a method of treating inflammation. These compounds are:

Q 0 A G om X Rs wherein (I) r, may be hydroxy,

amino,

lower alkoxy (such as methoxy, ethoxy, butoxy,

pentoxy, etc.)

loweralkylamino (such propylamino, pentylamino),

di(lower alkyl)amino (such as dimethylamino,

dibutylamino, propylpentylamino) diloweralkylaminoloweralkylamino,

diloweralkylaminoloweralkoxy,

hydroxyloweralkoxy (such as 3-hy,droxypropoxy,

2-hydroxypropoxy, 4-hydroxybutoxy),

polyhydroxyloweralkoxy (such as 2,3-dihydroxy propoxy, 2,3,4,5,6-pentahydroxyhexyloxy),

loweralkoxyloweralkoxy (such as ethoxyethoxy phenylloweralkoxy (benzyloxy, phenethoxy),

phenoxy,

substituted phenoxy (such as loweralkoxyphenoxy, diloweralkylarninophenoxy, halophenoxy, or loweralkanoylaminophenoxy,

loweralkanoylamino-loweralkoxy,

hydrazine, hydroxylamino,

N-morpholino,

anilino,

hydroxyloweralkylamino and a naturally occuring amino acid radical as methylamino,

LII

with attachment at the N, such as glycine, phenylalanine, proline, methionine and taurine; R is hydrogen acyl (preferably lower acyl such as formyl, acetyl,

propionyl, butyryl, etc. alkyl (preferably loweralkyl such as methyl, ethyl,

propyl, isopropyl, butyl, pentyl, etc.), alkoxy carbonyl (preferably loweralkoxy carbonyl such as methoxycarbonyl, ethoxycarbonyl, hexyloxycarbonyl, etc.) wherein the 0R group is always ortho to the COOH group; R is hydrogen,

halogen (such as chloro, bromo, fluoro, or iodo,

preferably fluoro or chloro), haloalkyl (preferably haloloweralkyl trifluoromethyl, etc. alkyl (preferably loweralkyl, such as methyl, ethyl, propyl, isopropyl, butyl, pentyl, etc.), cycloalkyl (such as cyclopropyl, cyclobutyl,

cyclopentyl, cyclohexyl and cycloheptyl), alkoxy (preferably loweralkoxy such as methoxy,

ethoxy, isopropoxy or butoxy), and X is hydrogen,

hydroxy, alkoxy (preferably loweralkoxy such as methoxy,

ethoxy, isopropoxy or butoxy, etc. acyloxy (such as benzoyloxy, acetoxy or propionoxy) Y halogen (such as chloro, bromo, fluoro or iodo,

preferably fluoro or chloro),

such as haloalkyl (preferably haloloweralkyl such as trifluoromethyl, etc.), 7

nitro,

amino,

alkylamino (preferably lower alkylamino such as methylamino, propylamino, pentylarnino, etc.

dialkylamino (preferably diloweralkylamino such as dimethylamino, dibutylamino, propyl-pentylamino, etc.

acylarnino (preferably lower acylamino such as formylamino, acetylamino,. propionylamino, butyrylamino, etc. mercapto,

dialkylaminoalkyl, (preferably diloweralkylaminoloweralkyl such as diethylarninoethyl etc.),

hydroxyalkyl (preferably hydroxyloweralkyl such as hydroxymethyl, hydroxyethyl, hydroxypropyl, etc.),

alkoxyalkyl (preferably loweralkoxyloweralkyl such as methoxymethyl, methoxyethyl, ethoxyethyl, ethoxypropyl, etc.

mercaptoalkyl (preferably mercaptoloweralkyl such as mercaptomethyl, mercaptoethyl, etc.

alkylmercaptoalkyl (preferably loweralkylmercaptoloweralkyl such as methylmercaptomethyl,

ethylmercaptoethyl, ethylmercaptopropyl, etc.),

cyano,

carboxy,

carboalkoxy (carbomethoxy, carboethoxy, etc.),

carbamoyl,

aryl (such as phenyl, tolyl, salicyl or halophenyl) aralkyl (such as benzyl, phenethyl, etc.)

aryloxy,

aralkoxy,

NRSO where R is hydrogen or lower alkyl, and the A radical is connected to the 4 or 5 position of the salicylic acid moiety, and the non toxic pharmaceutically acceptable salts thereof. Also the compounds of the above invention wherein X is hydroxy,

haloalkyl,

mercapto,

alkylmercapto,

alkylsul fonyl,

alkylamino,

diloweralkylamino,

alkylaminoalkyl,

mercaptoalkyl,

alkylme rcaptoalkyl,

carboalkoxy,

carbamyl,

aryl,

aralkyl,

aryloxy,

aralkoxy,

acetyl, are novel compounds and represent a preferred embodiment of this invention.

Preferred compounds of this invention which can be used in a method of treatment are those of Formula I wherein R, is hydroxy,

lower alkoxy,

dimethylaminoethoxy diethylaminoethoxy and simple amines such as amino, lowera'lkylamino,

diloweralkylamino and morpholino, R is hydrogen,

acetyl,

lower alkyl (lower)alkoxycarbonyl; alkoxycarbonyl;

R is hydrogen,

halogen,

lower alkyl trifluoromethyl,

lower alkoxy;

X is halo,

loweralkoxy,

diloweralkylamino,

loweralkylthio and the oxidation products of loweralkylthio; such as loweralkylsulfonyl and loweralkylsulfinyl, and A is as above defined.

The preferred novel compounds are those preferred compounds described immediately above except that X is limited to fluoro, diloweralkylamino, CH;,SO,

and CH S--.

Some representative preferred compounds which can be used in a method of treatment are those listed below, and those listed under representative preferred novel compounds.

[5-(p-chlorophenylsulfonamido )-salicylic acid; 5(p-chlorophenylsulfamyl)-salicylic acid;]

Furthermore, representative compounds which are novel compounds are those listed below;

5-(m-, 0- or p-fluorophenylsulfonamido)-salicylic acid, 5-[N-(m-, 0- or p-methylsulfinylphenylsulfamyl)]-salicylic acid, acid, 5-(m-, 0- or p-methyl'sulfonylphenylsulfonamido)-salicylic acid,

5-(o-, mor p-methylaminophenylsulfonamido)-salicylic acid 5-[N-(m-, 0- or p-trifluoromethylphenylsulfamyl)]-salicylic acid,

4-[N-(m-, por o-fluorophenylsulfamyl)]-salicylic acid, etc.

We have found that the compounds of Formula I have anti-inflammatory activity and are effective in the prevention and inhibition of edema and granuloma tissue formation as shown by reduction of edema in the rats foot induced by the injection of an inflammatory (phlogistic) agent into the rats foot.

The compounds of the instant invention can be used to treat inflammation by reducing inflammation and relieving pain'in such diseases as rheumatoid arthritis, osteoarthritis, gout, infectious arthritis and rheumatic fever.

The compounds of Formula I also have anti-pyretic and analgesic activity and would be administered and used in the same manner and in the same dosage ranges as if they were being used to treat inflammation as discussed further on.

The treatment of inflammation in accordance with the method of the present invention is accomplished by orally administering to patients a composition of a compound of Formula I, particularly the especially preferred compounds in a non-toxic pharmaceutically acceptable carrier, preferably in tablet or capsule form.

The non-toxic pharamaceutical carrier may be, for example, either a solid or a liquid. Exemplary of solid carriers are lactose, corn starch, gelatin, talc, sterotix, stearic acid, magnesium stearate, terra alba, sucrose, agar, pectin, cab-o-sil and acacia. Exemplary of liquid 0- or p-fluorophenylsulfamyl)]-salicylic carriers are peanut oil, olive oil, sesame oil and water.

Similarly, the carrier or diluent may include a time delay material such as glyceryl monostearate or glyceryl distearate alone or with a wax.

Several pharmaceutical forms of the therapeutically useful compositions can be used. For example, if a solid carrier is used, the compositions may take the form of tablets, capsules, powders, troches or lozenges, prepared by standard pharmaceutical techniques. lf a liquid carrier is used, the preparation may be in the form of a soft gelatin capsule, a syrup or a liquid suspension.

The active compounds of Formula I and of the compositions of this invention are present in an amount sufficient to treat inflammation, that is to reduce inflammation. Advantageously, the composition will contain the active ingredient, namely, the compounds of Formula I in an amount of from about 1 mg. to 100 mg. per kg. body weight per day (50 mg. to 7 g. per patient per day), preferably from about 2 mg. to 50 mg./kg. body weight per day 100 mg. to 3 g. per patient per day).

The method of treatment of this invention comprises internally administering to a patient (animal or human), a compound of Formula I, particularly an especially preferred compound admixed with a non-toxic pharmaceutical carrier such as exemplified above. The compounds of Formula I and particularly the especially preferred compounds will be present in an amount of from 1 mg. to 100 mg./kg. body weight per day, preferably from about 2 mg. to about 50 mg. per kilogram body weight per day and especially from 4 mg. to 20 mg./kg. body weight per day. The most rapid and effective anti-inflammatory effect is obtained from oral administration of a daily dosage of from about 4 to 20 mg./kg./day. It should be understood, however, that although preferred dosage ranges are given, the dose level for any particular patient depends upon the activity of the specific compound employed. Also many other factors that modify the actions of drugs will be taken into account by those skilled in the art in the therapeutic use of medicinal agents, particularly those of Formula I, for example, age, body weight, sex, diet, time of administration, route of administration, rate of excretion, drug combination, reaction sensitivities and severity of the particular disease.

Compounds of this invention may be prepared according to the following flow diagrams:

OH OH l 1 COOH Ra I) I S0 01 (III) I V) M OH NH2 OH Ra R: I

-COOH COOH D'IH (V) (VI) (VII) The substituted phenylsulfamyl compounds of Formula VII can be prepared by taking a 5-chlorosulfonylsalicylic acid compound (Formula V) and reacting it with an aniline compound (Formula VI) to form the desired substituted sulfamyl salicylic acid compound (Formula VII). Various wherein X and R are the various group defined can be prepared by starting with the appropriately substituted starting materials. Details of the various reaction processes are shown in the examples.

The compounds of this invention wherein R is a group such that an ester is the final compound (i.e., R is alkoxy) are prepared by any esterification procedure using an esterifying agent containing the appropriate R group. For example, the salicylic acid compounds of this invention may be reacted with the appropriate lower alkanol (preferably methanol) in the presence of a strong acid such as HCl or sulfuric acid and the like to fonn the desired compound. The reaction may occur at room temperature over an extended period of time or at elevated temperatures.

The compounds of this invention wherein R is a group such that an amide is the final compound (i.e., where R, is amino or substituted amino) may be prepared by any suitable amidation reaction. For example, the salicylic acid compound (preferably the methyl or ethyl ester) may be reacted with ammonia, ammonium hydroxide or an amine compound at any suitable temperature (room temperature to reflux). When the amino group is desired, it is preferred to carry out the reaction with ammonia in a bomb at temperatures about C. to form the desired R (amino) compound.

The salts of the final acid compound of this invention may be prepared by any of the well-known metathesis procedures. For example, the salicylic acid compound may be reacted with an inorganic base such as sodium hydroxide, potassium hydroxide etc. or with an amine such as N-N -diethylan'iinoethanol, etc. and the like.

Other substituted sulfamyl or sulfonamido salicylic acid compounds, particularly those having substituents in the phenyl or in the salicylic acid portion of the molecule can be prepared from related substituted salicylic acid compounds by conventional procedures shown in the prior art.

Following are a list of examples which describe this invention in greater detail. The examples should be construed as illustrations of the invention and not limitations.

EXAMPLE 1 5-[N-(P-Fluorophenylsulfamyl)]salicylic acid An intimate mixture of 5-(chlorosulfonyl)salicylic acid (0.01 m.), p-fluoroaniline (0.01 'm.) and anhydrous sodium acetate (0.01 m.) is heated to C. and kept at this temperature for two hours, protected from moisture with a calcium chloride drying tube. The mixture is cooled, dissolved in dilute sodium carbonate solution, filtered, acidified, and the S-[N-(pfluorophenylsulfamyl)]-salicylic acid collected.

The above reaction can also be carried out using a solvent as diluent, and other X-substituted anilines in place of p-fluoroaniline.

When 0- or m-fluoroaniline, m-(trifluoromethyl) aniline and other appropriately substituted anilines are substituted compounds used in place of p-fluoroaniline in the above example, the corresponding sulfonamides are obtained.

The various 4[N-(p-substituted phenyl sulfamyl)]- salicylic acid compounds can be prepared by using the appropriate 4-(chlorosulfonyl) salicylic acids in place of the -(chlorosulfonyl) salicylic acid compounds. By using the appropriately substituted N-alkylanilines in place of p-fluoroaniline used above, there are obtained the appropriately substituted N-alkyl sulfonamides.

EXAMPLE 2 5-[N-(p-Fluorophenylsulfamyl)] salicylic acid amides A mixture of methyl 5[N-(p-fluorophenylsulfamyl)]- salicylate and concentrated ammonium hydroxide is heated at 100 C. in a sealed tube for 6 hours. After cooling, water is added and the S-[N-(p-fluorophenylsulfamyl)]salicylamide is collected.

When monomethylamine, dimethylamine, ethylamine, diethylamine, morpholine, piperidine, etc. are used in place of ammonium hydroxide, the corresponding amides are obtained.

Other appropriately substituted starting materials can be used and the appropriately substituted amide will be formed.

Similarly, 5-(p-fluorophenylsulfonamido)salicylamid es or substituted salicylamides can be prepared by using 5-(p-fluorophenylsulfonamido)salicylic acid as the starting material in place of S-[N-(p-fluorophenylsulfamyl)]-salicylic acid used above.

EXAMPLE 3 2-Acetoxy-5-[N-(p-fluorophenylsulfamyl)]benzoic acid To a mixture of 5-[N-(p-fluorophenyl sulfamyl)]salicylic acid (.04 mole) in ml. of anhydrous pyridine is added 28 ml. of acetic anhydride and the resultant mixture heated on the steam bath for 1.5 hours. The mix ture is kept free from moisture during this time. On cooling, the mixture is added to a stirred 500 ml. portion of water, the aqueous system extracted well with chloroform, the chloroform extracts washed with 1N hydrochloric acid, water, and then dried over anhydrous magnesium sulfate. Concentration of the filtered solution yields 2-acetoxy-5-[N-(p-fluorophenylsulfamyl)] benzoic acid.

When propionic or butyric anhydride is used in place of acetic anhydride in the above example, the corresponding propionoxy or butyroxy compounds are obtained. When other appropriately substituted salicylic acids are used as starting materials in place of the S-[N- (p-fluorophenylsulfamyl)]-salicylic acid used above or S-(p-fluorophenyl)sulfonamido salicylic acid used below, the corresponding acyloxybenzoic acids are obtained.

When 5-(p-fluorophenylsulfonamido)salicylic acid is used in place of 5-[N-(p-fluorophenylsulfamyl)]salicylic acid used above and the same procedure followed, there is produced 2-acetoxy-5-(p-fluorophenyl sulfonamido)benzoic acid.

EXAMPLE 4 N,N-diethylaminoethyl sulfamyl)]-salicylate lowed to stand overnight. The precipitated dicyclohexylurea is removed by filtration. The filtrate is concentrated in vacuo, the residue partitionedbetween ether and hydrochloric acid, the layers separated, the aqueous layer washed once with fresh ether and neutralized with saturated bicarbonate solution. Extraction with chloroform, followed by removal of the chloroform in vacuo yields N,N-diethylaminoethyl S-[N-(pfluorophenyl-sulfamyl)] salicylate.

Other esters can be prepared by following the above procedure but using the appropriately substituted starting materials.

EXAMPLE 5 5-p-Fluorophenylsulfonamido)salicylic acid. i

To 7.65 g. of S-amino salicylic acid in 6% aqueous sodium hydroxide solution ml.) is added a mixture of p-fluorobenzenesulfonyl chloride (10 g.) and 'water, and the mixture shaken at 4050 C. for 5 hours. 5 G. of sodium hydroxide is added, the mixture shaken for a further three hours at 60 C., the mixture allowed to cool, treated with carbon, filtered, the pH adjusted to '3, and the 5-(p-fluorophenylsulfonamido)- salicylic acid collected.

The above reaction may also be carried out using pyridine (or similar base) at ca 40 C., as solvent and base.

When oor m-fluorobenzenesulfonyl chloride, mtrifluoromethylbenzenesulfonyl chloride and other X- substituted benzenesulfonyl chlorides are used in place of p-fluorobenzenesulfonyl chloride in the above example, the corresponding appropriately substituted sulfonamido compounds are obtained.

When using 4-amino salicylic acid in place of 5- amino salicylic acid used above, there are obtained the appropriately substituted 4-(benzenesulfonamido)salicylic acid compounds. Similarly, if one uses the appropriately substituted N-methylaminosalicylic acid in place of S-aminosalicylic acid used above, there are produced the appropriately substituted Nmethylsulfonamides. Y

EXAMPLE 6 Sodium 5-(p-Fluorophenylsulfonamido)salicylate Solutions of 5-(p-fluorophenylsulfonamido salicylic acid in methanol and one equivalent of sodium hydroxide in water are mixed, heated to solution, filtered and the filtrate concentrated in vacuo to yield sodium S-(pfiuorophenylsulfonamido)salicylate.

When potassium hydroxide is used in place of sodium hydroxide in the above example the corresponding potassium salt is obtained.

The sodium or potassium S-[N-(p-fluorophenylsulfamyl)]salicylate can be prepared by following the procedure above but using S-[N-(p-fluorophenylsulfamyl)]-salicylic acid in place of S-(p-fluorophenylsulfonamido)-salicylic acid used above.

We claim:

1. A method of treating inflammation in a patient in need of such treatment which comprises oral administration to said patient of an efiective amount of a compound of the formula:

COOH

or a pharmaceutically acceptable non-toxic salt wherein X is chloro, fluoro, lower alkylsulfonyl, lower alkylamino, or trifluoromethyl, wherein the SO NH radical is connected to the 4 or 5 position of the salicylic'acid moiety.

3. A method of treating inflammation in a patient in need of such treatment which comprises oral administration to said patient of an effective amount of a compound of formula:

COOH

wherein the SO NH radical is connected to the 4 or 5 position of the salicylic acid moiety.

4. The method of claim 3, wherein the compound is 5-(p-fluorophenylsulfonamido)salicylic acid.

UNITED STATES PATENT OFFICE CERTIFICATE OF CORRECTION Patent No. 3,700,773 Dated October 2L 1972 Inventor-(s) It is certified that error appears in the above-identified patent and that said Letters Patent are hereby corrected as shown below:

In the title, "salicyclic" should be salicylic-.

Signed and sealed this 13th day of March 1973 (SEAL) Attest EDWARD M. FLETCHER,JR. ROBERT GOTTS CHALK Attesting Officer Commissioner of Patents 

2. A method of treating inflammation in a patient in need of such treatment which comprises oral administration of an effective amount of a compound of the formula:
 3. A method of treating inflammation in a patient in need of such treatment which comprises oral administration to said patient of an effective amount of a compound of formula:
 4. The method of claim 3, wherein the compound is 5-(p-fluorophenylsulfonamido)salicylic acid. 